WO2003022836A1 - Composes heterocycliques azotes, et leur utilisation comme inhibiteurs de proteine raf - Google Patents

Composes heterocycliques azotes, et leur utilisation comme inhibiteurs de proteine raf Download PDF

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WO2003022836A1
WO2003022836A1 PCT/EP2002/009942 EP0209942W WO03022836A1 WO 2003022836 A1 WO2003022836 A1 WO 2003022836A1 EP 0209942 W EP0209942 W EP 0209942W WO 03022836 A1 WO03022836 A1 WO 03022836A1
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alkyl
hydrogen
pharmaceutically acceptable
optionally substituted
compound
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PCT/EP2002/009942
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Mark James Bamford
David Kenneth Dean
Antoinette Naylor
Andrew Kenneth Takle
David Matthew Wilson
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Smithkline Beecham Plc
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Priority to EP02779309A priority Critical patent/EP1432702B1/fr
Priority to JP2003526911A priority patent/JP2005505563A/ja
Priority to DE60214019T priority patent/DE60214019T2/de
Priority to US10/488,579 priority patent/US7297693B2/en
Publication of WO2003022836A1 publication Critical patent/WO2003022836A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to novel compounds and their use as pharmaceuticals, particularly as Raf kinase inhibitors for the treatment of neurotraumatic diseases, cancer chronic neurodegeneration, pain, migraine and cardiac hypertrophy.
  • Raf protein kinases are key components of signal transduction pathways by which specific extracellular stimuli elicit precise cellular responses in mammalian cells.
  • Activated cell surface receptors activate ras/rap proteins at the inner aspect of the plasma-membrane which in turn recruit and activate Raf proteins.
  • Activated Raf proteins phosphorylate and activate the intracellular protein kinases MEK1 and MEK2.
  • activated MEKs catalyse phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK).
  • a variety of cytoplasmic and nuclear substrates of activated MAPK are known which directly or indirectly contribute to the cellular response to environmental change.
  • Three distinct genes have been identified in mammals that encode Raf proteins; A-Raf, B-Raf and C-Raf (also known as Raf-1) and isoformic variants that result from differential splicing of mRNA are known.
  • Inhibitors of Raf kinases have been suggested for use in disruption of tumor cell growth and hence in the treatment of cancers, e.g. histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer and pancreatic and breast carcinoma; also in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischemic events, including cerebral ischemia after cardiac arrest, stroke and multi-infarct dementia and also after cerebral ischemic events such as those resulting from head injury, surgery and/or during childbirth; also in chronic neurodegeneration such as Alzheimer's disease and Parkinson's disease; also in the treatment of pain, migraine and cardiac hypertrophy.
  • cancers e.g. histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer and pancreatic and breast carcinoma
  • disorders associated with neuronal degeneration resulting from ischemic events including cerebral ischemia after cardiac arrest, stroke and multi-infarct dementia and also after cerebral
  • X is O, CH 2 , CO, S or NH, or the moiety X-R 1 is hydrogen; Yi and Y 2 independently represent CH or N;
  • R 1 is hydrogen, C j _ 6 alkyl, C 3-7 cycloalkyl, aryl, arylC j 6 alkyl-, heterocyclyl, heterocyclylC, 6 alkyl-, heteroaryl, or heteroarylC, 6 alkyl-, any of which, except hydrogen, maybe optionally substituted;
  • R 2 is CO R 6 R 7 ;
  • R and R independently represent hydrogen, C._ 6 alkyl, C 3 . 7 cycloalkyl, aryl, arylC, 6 alkyl, heteroaryl, heteroarylC, 6 alkyl, heterocyclyl, or heterocyclylC,. 6 alkyl, any of which except for hydrogen may be optionally substituted, or R 6 and R 7 together with the nitrogen atom to which they are attached form a 3- to 12-membered monocyclic or bicyclic ring optionally including upto three heteroatoms selected from O, N or S wherein said ring may be optionally substituted;
  • Ar is a group of the formula a) or b):
  • A represents a fused 5- to 7-membered ring optionally containing up to two heteroatoms selected from O, S and NR 5 , wherein R 5 is hydrogen or Cj- ⁇ alkyl, which ring is optionally substituted by up to 2 substituents selected from halogen, C ⁇ -6 alkyl, hydroxy, Ci. 6 alkoxy or keto;
  • R 3 and R 4 are independently selected from hydrogen, halogen, C ⁇ -6 alkyl, aryl, aryl . ⁇ alkyl, C I-6 alkoxy, C ⁇ . 6 alkoxyC ⁇ -6 alkyl, haloC ⁇ . 6 alkyl, arylC ⁇ -6 alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N-C ⁇ -6 alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-C ⁇ _ 6 alkylcarbamoyl, .
  • the double bond indicated by the dotted lines of formula (I), represents the possible regioisomeric ring forms of the compounds falling within the scope of this invention, the double bond being between the non-heteroatoms.
  • the hydroxyimino moiety can be positioned on any of carbon atoms of the non-aromatic ring in groups a) and b).
  • the hydroxyimino moiety can exist as either the E or Z isomer or as a mixture of both.
  • Alkyl and alkenyl groups referred to herein, individually or as part of larger groups e.g. alkoxy, may be straight or branched groups containing up to six carbon atoms and are optionally substituted by one or more groups selected from the group consisting of aryl, heteroaryl, heterocyclyl, C ⁇ -6 alkylthio, arylC ⁇ -6 alkoxy, arylC 1-6 alkylthio, amino, mono- or di- .
  • Cycloalkyl and cycloalkenyl groups referred to herein include groups having from three to seven ring carbon atoms and are optionally substituted as described hereinabove for alkyl and alkenyl groups.
  • Optional substituents for alkyl, alkenyl, cycloalkyl and cycloalkenyl groups include aryl, heteroaryl, heterocyclyl, C ⁇ -6 alkoxy, C ⁇ -6 alkylthio, arylC ]-6 alkoxy, arylC ⁇ -6 alkylthio, amino, mono-or di-C ⁇ . 6 alkylamino, aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amide, ureido, quanidino, C ⁇ -6 alkylquanidino, amidino, Ci.
  • the substituents are mono-or di-Ci. 6 alkylamino, heterocycloC ⁇ . 6 alkylamino or C 2-6 acylamino.
  • the optional substituent contains a water-solubilising group; suitable solubilising moieties will be apparent to those skilled in the art and include hydroxy and amine groups. Even more preferably the optional substituent includes amino, mono- or di-C ⁇ _ 6 alkylamino, amine containing heterocyclyl, or hydroxy or any combination thereof.
  • aryl includes, unless otherwise defined, single and fused rings suitably containing from 4 to 7, preferably 5 or 6, ring atoms in each ring, which rings, may each be unsubstituted or substituted by, for example, up to three substituents.
  • Suitable aryl groups include phenyl and naphthyl, such as 1-naphthyl or 2-naphthyl.
  • the term "monocyclic ring” means a 3 to 7 membered ring system for example phenyl, pyrrole, pyrroline, pyrrolidine, piperidine, mo ⁇ holine, thiomo ⁇ holine, piperizine, indole or indoline.
  • the term "bicyclic ring” means a 7 to 12 membered fused ring system e.g napthyl.
  • heteroC ⁇ -6 alkyl- means a C ]-6 carbon chain wherein the end carbon atom in the chain is substituted by a heteroatom selected from N, O, or S for example .
  • C ⁇ -6 alkylheteroC ⁇ .6alkyl means a C 3- i 3 alkyl chain wherein one of the carbon atoms has been replaced with a heteroatom selected from N, O, or S, for example C ⁇ -6 alkylaminoC ⁇ -6 alkyl or C ⁇ -6 alkylaminodiC ⁇ -6 alkyl, C ⁇ -6 alkyloxyC ⁇ . 6 alkyl-, C I-6 alkylthioC ⁇ -6 alkyl-, or C ⁇ _ alkylthiodiC ⁇ -6 alkyl.
  • heterocyclyl includes, unless otherwise defined, non- aromatic, single or fused, saturated or unsaturated, rings suitably containing up to four heteroatoms in each ring, each of which is selected from O, N and S, which rings, may be unsubstituted or substituted by, for example, up to three substituents.
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • heterocyclyl groups include pyrrolidine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine, imidazolidine and pyrazolidine.
  • heteroaryl includes, unless otherwise defined, mono- and bicyclic heteroaromatic ring systems comprising up to four, preferably 1 or 2, heteroatoms each selected from O, N and S. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a bicyclic heteroaromatic ring system may include a carbocyclic ring. Examples of heteroaryl groups include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole and benzimidazole.
  • the term "mono-cyclic” means an aromatic or heteroaromatic group having a 3 to 8 membered ring system for example phenyl, pyridine or pyran.
  • the term "bicyclic ring” means an aromatic or heteroaromatic fused ring system in which at least one of the rings is aromatic or heteroaromatic for example naphthyl, indole, benzofuran, indene, fused phenylcyclohexane, or fused phenyl cyclopentane.
  • Aryl, heterocyclyl, heteroaryl groups and mono and bicyclic ring systems may be optionally substituted by preferably up to three substituents.
  • Suitable substituents include halogen, hydroxy, C ⁇ -6 alkyl, aryl, arylC ⁇ -6 alkyl, C ⁇ -6 alkoxy, C ⁇ -6 alkoxyC ⁇ .
  • the optional substituent contains a water-solubilising group; suitable solubilising moieties will be apparent to those skilled in the art and include hydroxy and amine groups. Even more preferably the optional substituent includes amino, mono- or di- . 6 alkylamino, amine containing heterocycle or hydroxy or any combination thereof. Other preferred substituents are C ⁇ -6 alkyl and C ⁇ . 6 alkoxyC ⁇ . 6 alkyl.
  • halo represents fiuoro, chloro, bromo or iodo.
  • X is preferably ⁇ H or X-R 1 is preferably hydrogen.
  • R 1 is preferably hydrogen or C ⁇ -6 alkyl.
  • X-R 1 is preferably hydrogen.
  • R 1 is preferably hydrogen or C ⁇ -6 alkyl.
  • R n is hydrogen.
  • X-R 1 is hydrogen
  • X ! or X 2 is S or O, most preferably O.
  • A is preferably a fused 5 membered ring optionally containing up to two heteroatoms selected from O, S and ⁇ R 5 , wherein R 5 is hydrogen or C ⁇ -6 alkyl, which ring is optionally substituted by up to 2 substituents selected from halogen, C ⁇ -6 alkyl, hydroxy, C ⁇ -6 alkoxy or keto. Even more preferably A is a fused 5 membered ring.
  • R 6 and R 7 are independently selected from hydrogen, C ⁇ -6 alkyl, aryl, heterocyclic and heterocyclicC ⁇ -6 alkyl wherein any of the groups except hydrogen may be optionally substituted or R 6 and R 7 together with the nitrogen atom to which they are attached form a 3- to 7-membered monocyclic optionally including upto three heteroatoms selected from O, ⁇ or S wherein said ring may be optionally substituted.
  • the compounds of the invention are of formula (H); wherein R 1 , X, Y b Y 2 , R 3 , Xi, X 2 , R 2 and R 4 are as defined for compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • the compounds of formula (I) preferably have a molecular weight of less than 800.
  • Preferred substituents for the group Ar include halo, hydroxy, hydroxyC ⁇ -6 alkyl, hydroxyimino-C ⁇ -6 alkyl and C ⁇ -6 alkoxy.
  • compositions according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivatives includes any pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • salts of the compounds of formula (I) should be pharmaceutically acceptable.
  • suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described inJ. Pharm. Set, 1911, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (T) and are included within the scope of this invention.
  • the compounds of this invention may be in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • the invention extends to all isomeric forms including stereoisomers and geometric isomers of the compounds of formula (1) including enantiomers and mixtures thereof e.g. racemates.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the O 03/022836
  • compounds of this invention may be prepared by a sequential transition metal catalysed cross-coupling procedure on a 2,3-dihalo heterocycle, as shown in Scheme 1; this is particularly applicable for furan or thiophene derivatives, i.e. when either X] or X 2 are O or S.
  • Suzuki coupling of pyridine-4-boronic acid with 2,3-dibromofuran-5-carboxylic acid t-butyl ester (1) preferentially results in the formation of the 2-(4-pyridyl) derivative (2).
  • Subsequent Suzuki reaction with an indanone boronic acid derivative (3, wherein PG is O, ⁇ - OMe or another ketone protecting group) then generates the derivative (4).
  • ester group may be converted into an amide group using appropriate conventional functional group interconversion procedures and the group PG converted into an hydroxyimino group as in (5). It will also be appreciated, to one skilled in the art, that the above cross-coupling reactions may be carried out in reverse order giving access to the regioisomeric heterocycles (6).
  • labile functional groups in the intermediate compounds e.g. hydroxy, carboxy and amino groups
  • a comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (Wiley-Interscience, New York, 2nd edition, 1991).
  • the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I).
  • Libraries of compounds of formula (I) may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of formula (I), or pharmaceutically acceptable salts thereof.
  • compositions of formula (I) and (U) may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • novel carboxylic esters and the corresponding acids of formula (lTf) which are used as intermediates in the synthesis of the compounds of formula (I) and (U) also form part of the present invention:
  • X, Yi, Y 2 , R 1 , R 3 , Ar, Xj and X 2 are as defined for compounds of formula (I) and R is hydrogen, C, 6 alkyl or arylC, 6 alkyl.
  • the compounds of formula (1) and their pharmaceutically acceptable derivatives are useful for the treatment and/or prophylaxis of disorders in which Raf kinases, in particular B-Raf kinase, are implicated.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof as an inhibitor of B-Raf kinase.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives are useful in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischemic events, cancer, as well as chronic neurodegeneration, pain, migraine and cardiac hypertropy.
  • a method of treatment or prophylaxis of a neurotraumatic disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by a neurotraumatic event.
  • Neurotraumatic diseases/events as defined herein include both open or penetrating head trauma, such as caused by surgery, or a closed head trauma injury, such as caused by an injury to the head region.
  • ischemic stroke particularly to the brain area, transient ischemic attacks following coronary by-pass and cognitive decline following other transient ischemic conditions.
  • Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
  • the compounds of the invention may also be used in the treatment or prophylaxis of cancers. It is suggested that the compounds are effective in tumors that have activating B-Raf mutations (V599E) as well as tumors that are activated by Ras mutation. Mutations may occur in the Ras family members such as Kras2 with mutation G13D. Furthermore compounds of the invention may be used in the treament or prophylaxis of colorectal cancer and melanoma
  • a method of treatment or prophylaxis of a mammal who is suffering from or susceptible to cancer which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prophylactic or therapeutic treatment of cancers.
  • the compounds of formula (I) and pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions.
  • combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, and the use of at least one other cancer treatment method.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, and at least one other pharmaceutically active chemotherapeutic agent.
  • These include existing and prospective chemotherapeutic agents.
  • the compound(s) of formula (1) and the other pharmaceutically active chemotherapeutic agent(s) may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active chemotherapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • cell cycle specific anti-neoplastic agents include, but are not limited to, dite ⁇ enoids such as paclitaxel and its analog docetaxel; tubulin poisons such as taxol/taxane or vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine; antimetabolites such as allopurinol, fludarabine, methotrexate, cladrabine, cytarabine, mercaptopurine, gemcitabine, and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, topotecan, and
  • anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene
  • progestrogens such as megestrol acetate
  • aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane
  • antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate
  • LHRH agonists and antagagonists such as goserelin acetate and luprolide, testosterone 5a- dihydroreductase inhibitors such as finasteride
  • metalloproteinase inhibitors such as marimastat
  • antiprogestrogens mitoxantrone, 1-asparaginase, urokinase plasminogen activator receptor function inhibitors; inhibitors or c-kit and
  • hepatocyte growth factor such as prednisone and decadron
  • radiation sensitizers such as temazolamide
  • growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor; erb-B2, erb- B4, epidermal growth factor receptor (EGFR) and platelet derived growth factor receptors
  • PDGFR blood pressure regulator factor receptor 4
  • angiogenesis such as inhibitors of the function of Ephrin receptors (such as, EphB4), vascular endothelial growth factor receptors (VEGFR) and the angiopoietin receptors (Tiel and Tie2)
  • EphB4 vascular endothelial growth factor receptors
  • VEGFR vascular endothelial growth factor receptors
  • Tiel and Tie2 angiopoietin receptors
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • a method of treatment or prophylaxis of chronic neurodegeneration, pain, migraine or cardiac hypertrophy, in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prophylactic or therapeutic treatment of chronic neurodegeneration, pain, migraine or cardiac hypertrophy.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier.
  • the compounds of formula (I) may conveniently be administered by any of the routes conventionally used for drug administration, for instance, parenterally, orally, topically or by inhalation.
  • the compounds of formula (I) may be administered in conventional dosage forms prepared by combining it with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the form and character of the pharmaceutically acceptable carrier is dictated by the amount of compound of formula (I) with which it is to be combined, the route of administration and other well-known variables.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25mg to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or nonaqueous liquid suspension.
  • the compounds of formula (1) are preferably administered parenterally, that is by intravenous, intramuscular, subcutaneous, sublingual, intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the intravenous form of parenteral administration is generally preferred.
  • the compounds may be administered as a bolus or continuous infusion e.g. of 6 hours up to 3 days. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the compounds of formula (I) may also be administered orally. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the compounds of formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as aerosol formulations, may be prepared by conventional techniques.
  • the compounds of formula (I) may also be administered topically, that is by non- systemic administration. This includes the application of the inhibitors externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 to 15mg/kg.
  • the daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 to 15mg/kg.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of the inhibitors will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the inhibitors given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. In the case of pharmaceutically acceptable salts the above figures are calculated as the parent compound of formula (I).
  • THF means tetrahydrofuran
  • DMF means N,N-Dimethylformamide.
  • Step 1 The product of Step 1 (5.32g, 16.4 mmol), the product of Description 1 (4.03g, 19.7 mmol), potassium carbonate (13.6g, 98.4 mmol), triphenylphosphine (365 mg, 1.64 mmol) and palladium acetate (184mg, 0.8mmol) were dissolved in ethylene glycol dimethyl ether (100ml) and water (50ml). The mixture was then heated under reflux for 5 hours, cooled and filtered through a pad of celite. The filtrate was then washed with saturated sodium bicarbonate solution, water and brine.
  • Step 3 5-(l-Oxo-mdan-5-yl)-4-pyridin-4-yl-furan-2-carboxyIic acid hydrochloride salt
  • the title compound (2.32g, 84%) was prepared from the product from step 2 (3.17g, 7.83mmol) by the general 2 step method of description 2, steps 3 and 4; MS (ES + ) m/e 320 [M+H] +
  • Step 1 5- ⁇ 5-(l-Morpholin-4-yl-methanoyl)-2-pyridin-4-yl-fura ⁇ -3-yl]-mdan-l-one
  • the product of Description 2 178 mg, 0.5mmol
  • N-cyclohexylcarbodiimide,N'-methyl polystyrene resin 1.8mmol/g
  • 1-hydroxybenzotriazole hydrate 135mg, lmmol
  • Step 1 4-( ⁇ l-[4-(l-Oxo-indan-5-yl)-5-pyridin-4-yl-furan-2-yl]-methanoyl ⁇ -amino)- piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 4-(l-Hydroxyimino-indan-5-yl)-5-pyridin-4-yl-furan-2-carboxylic acid methyl- piperidin-4-yl-amide
  • the product from Step 1 (122mg, 0.24mmol) was stirred in trifluoroacetic acid (5 ml) and dichloromethane (5ml) at room temperature for 2 hours and the solution was then co-evaporated three times with dichloromethane.
  • the resulting residue was treated according to the general method of Example 1 Step 2 to give the title compound (0.02g, 20%); MS (AP+) m/e 416 (M+H) + .
  • Step 2 5-(l-Hydroxyimino-indan-5-yl)-4-pyridin-4-yl-furan-2-carboxylic acid (2- dimethylamino-ethyl)-methyl-amide
  • the title compound (0.051g, 26%) was prepared from the product of Stepl using the method of • Example 1 Step 2; MS (AP+ve): m/e 461 (M+H) + .
  • Step 1 5-(l-Oxo-indan-5-yl)-4-pyridin-4-yl-furan-2-carboxylic acid (2-amino-ethyl)-amide
  • Step 2 5-(l-Hydroxyimino-indan-5-yl)-4-pyridin-4-yl-furan-2-carboxylic acid (2-amino- ethyl)-amide
  • Step 2 4-Bromo-5-(l-methoxyimino-indan-5-yl)-thiophene-2-carboxylic acid methyl-(l- methyl-piperidin-4-yl)-amide
  • Step 1 The product of Step 1 (3.41g, 9 mmol), the product of Description 1 (1.85g, 9 mmol), potassium carbonate (7.46g, 54 mmol), triphenylphosphine (240 mg, 0.9 mmol), and palladium acetate (lOOmg, 0.45mmol) were dissolved in ethylene glycol dimethyl ether (50ml) and water (25ml).
  • the biphasic solution was heated at reflux for 36 hours, with vigorous stirring, cooled, then filtered through a pad of celite, which was thoroughly washed with ethyl acetate.
  • the two phase filtrate was separated and the organic phase washed with saturated sodium bicarbonate solution, water (x3) and brine.
  • Step 2 The product of Step 2 (670mg, 1.4 mmol), 4-pyridyl boronic acid (M. Lamothe et alJ. Med. Chem., 1997, 40, 3542) (189mg, 1.5 mmol), potassium carbonate (1.17g, 8.5 mmol), triphenylphosphine (37 mg, 0.14 mmol), and palladium acetate (16mg, 0.07 mmol) were dissolved in ethylene glycol dimethyl ether (15ml) and water (5ml). The biphasic solution was heated at reflux for 16 hours, with vigorous stirring, cooled, then filtered through a pad of celite, which was thoroughly washed with ethyl acetate.
  • 4-pyridyl boronic acid M. Lamothe et alJ. Med. Chem., 1997, 40, 3542
  • potassium carbonate (1.17g, 8.5 mmol
  • triphenylphosphine 37 mg, 0.14 mmol
  • step 3 The product of step 3 (476 mg lmmol) was dissolved in 5N hydrochloric acid (10 ml), dioxane (10ml) and acetone (5 ml) and heated at 80°C for 2 hours. The resulting solution was concentrated in vacuo and co-evaporated with ethanol (x3) to afford a crude solid. This was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (x2), and the combined organic extracts were washed with water (x3), brine, dried and evaporated in vacuo to a crude solid. This was purified by column chromatography (1:9:40 0.880 ammonia:thanol:dichloromethane) to afford title product (300 mg, 67%); MS (AP+) m/e 446 [M+H] +
  • step 4 The product of step 4 (300 mg, 0.8mmol) was heated at reflux in ethanol (10ml) containing hydroxylamine (50% aqueous solution) (1ml) for 1 hour. The solution was co-evaporated in ethanol (x3) to afford a crude solid. The product was purified twice by silica gel chromatography (1:9:40 0.880 ammonia:thanol: dichloromethane) to afford the title compound (80 mg, 22%); MS (AP+) m/e 461 [M+H] +
  • the kinase enzyme, fluorescent ligand and a variable concentration of test compound are incubated together to reach thermodynamic equilibrium under conditions such that in the absence of test compound the fluorescent ligand is significantly (>50%) enzyme bound and in the presence of a sufficient concentration (> 1 Ox Ki) of a potent inhibitor the anisotropy of the unbound fluorescent ligand is measurably different from the bound value.
  • the concentration of kinase enzyme should preferably be >lx K f .
  • the concentration of fluorescent ligand required will depend on the instrumentation used, and the fluorescent and physicochemical properties. The concentration used must be lower than the concentration of kinase enzyme, and preferably less than half the kinase enzyme concentration.
  • a typical protocol is:
  • Fluorescent ligand concentration 0.5 nM
  • Test compound concentration 0.5 nM - 100 uM
  • Kf dissociation constant for fluorescent ligand binding
  • the fluorescent ligand is the following compound:
  • Compounds of the invention have a K of less than 1 ⁇ M.
  • Results The compounds of the examples were found to be effective in inhibiting B-Raf mediated phosphorylation of GST-kdMEK substrate having IC 50 's of ⁇ 3 ⁇ M.
  • the activity of compounds as Raf inhibitors may also be determined by the assays described in
  • Raf/MEK/ERK kinase cascade high throughput screening and identification of selective enzyme inhibitors, Anal. Biochem. 268: 318-329 and AACR meeting New La 1998 Poster 3793.
  • the neuroprotective properties of B-Raf inhibitors may be determined by the following in vitro assay: Neuroprotective properties of B-Raf inhibitors in rat hippocampal slice cultures
  • Organotypic cultures provide an intermediate between dissociated neuronal cell cultures and in- vivo models of oxygen and glucose deprivation (OGD).
  • OGD oxygen and glucose deprivation
  • the majority of glial-neuronal interactions and neuronal circuitry are maintained in cultured hippocampal slices, so facilitating investigation of the patterns of death among differing cell types in a model that resembles the in vivo situation.
  • These cultures allow the study of delayed cellular damage and death 24 hours, or more, post-insult and permit assessment of the consequences of long-term alterations in culture conditions.
  • Bound PI shows increased emission at 635nm when excited at 540nm.
  • One PI fluorescence image and one white light image are taken and the proportion of cell death analysed.
  • the area of region CA1 is defined from the white light image and superimposed over the PI image.
  • the PI signal is thresholded and area of PI damage expressed as a percentage of the CA1 area. Correlation between PI fluorescence and histologically confirmed cell death has been validated previously by Nissl-staining using cresyl fast violet (Newell et al., J. Neurosci., 1995, 15, 7702-7711).
  • the anti-cancer properties of compounds of the invention may be determined by the following in vitro assays: Methylene Blue Growth Inhibition Assay (Assay 2)
  • HFF human foreskin fibroblasts
  • A375P human melanoma
  • SKMEL2, SKMEL3 colon carcinoma
  • RPMI Roswell Park Memorial Institute
  • FBS fetal bovine serum
  • HFF Dulbecco's modified Eagle Medium
  • MEM Minimum Essential Medium
  • Cells were harvested using 0.25 %trypsin l mM, EDTA, counted using a haemocytometer, and plated in 100 microliters of the appropriate media, at the following densities, in a 96-well tissue culture plate (Falcon 3075): HFF and A375P, 5,000 cells/well; all other cell lines, 10,000 cells/well.
  • HFF and A375P 5,000 cells/well
  • all other cell lines 10,000 cells/well.
  • compounds were diluted in RPMI containing 100 micrograms/ml gentamicin, at twice the final required concentration, from 10 mM stock solutions in dimethyl sulphoxide (DMSO).
  • DMSO dimethyl sulphoxide
  • RPMI containing 0.6% DMSO was added to control wells. Compounds diluted in. The final concentration of DMSO in all wells was 0.3%.
  • Cells were incubated at 37°C, 5% C0 2 for 3 days. Medium was removed by aspiration. Cell biomass was estimated by staining cells with 90 ⁇ l per well methylene blue (Sigma M9140, 0.5% in 50:50 ethanohwater) and incubation at room temperature for at least 30 minutes. Stain was removed, the plates rinsed by immersion in deionized water and air-dried.
  • HFF Human diploid foreskin fibroblasts
  • Colo 201 Human colon carcinoma cells were grown in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen / Life Technologies) containing 10% fetal bovine serum (FBS) and the antibiotics penicillin (100 Units/ml) and streotomycin (100 micrograms/ml) (Invitrogen / Life Technologies). Growth was at 37°C in humidified 5% C02 incubators in 75 cm 2 plastic flasks. Cells were harvested using 0.25% trypsin /l mM ethylenediaminetetraacetic acid (EDTA), resuspended in growth medium, and counted using a hemocytometer.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • EDTA ethylenediaminetetraacetic acid
  • IC50 was that concentration of compound that reduced cell viability to 50% of control (untreated) viability, as determined from plots of concentration vs percent viability.
  • HFF Human foreskin fibroblasts
  • ⁇ indicates IC 50 0.3-3 ⁇ M f indicates IC50 ⁇ 0.3 ⁇ M A375, Colo205 and SKMEL are reported as wild type (wt) for Ras status in the literature.
  • V599E indicates that the cell lines have activating BRaf mutation (V599E) ND represents not determined

Abstract

L'invention concerne des composés et leur utilisation comme médicaments, en particulier comme inhibiteurs de Raf kinase, pour le traitement des maladies neurologiques, du cancer, de la neurodégénérescence chronique, de la douleur, de la migraine et de l'hypertrophie cardiaque.
PCT/EP2002/009942 2001-09-05 2002-09-05 Composes heterocycliques azotes, et leur utilisation comme inhibiteurs de proteine raf WO2003022836A1 (fr)

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EP02779309A EP1432702B1 (fr) 2001-09-05 2002-09-05 Composes heterocycliques azotes, et leur utilisation comme inhibiteurs de proteine raf
JP2003526911A JP2005505563A (ja) 2001-09-05 2002-09-05 窒素含有ヘテロサイクリック化合物およびＲａｆ阻害剤としてのその使用
DE60214019T DE60214019T2 (de) 2001-09-05 2002-09-05 Stickstoff enthaltende heterozyklen und ihre verwendung als raf inhibitoren
US10/488,579 US7297693B2 (en) 2001-09-05 2002-09-05 Nitrogen-containing heterocyclic compounds and their use as Raf inhibitors

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WO2009025358A1 (fr) 2007-08-23 2009-02-26 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
WO2010064722A1 (fr) 2008-12-02 2010-06-10 Takeda Pharmaceutical Company Limited Dérivés de benzothiazole convenant comme agents anticancéreux
WO2010064611A1 (fr) 2008-12-01 2010-06-10 武田薬品工業株式会社 Composé hétérocyclique et applications
US8304557B2 (en) 2007-06-05 2012-11-06 Takeda Pharmaceutical Company Limited Fused heterocycle derivatives and use thereof
US8344135B2 (en) 2007-08-29 2013-01-01 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

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JP2003514906A (ja) * 1999-11-22 2003-04-22 スミスクライン ビーチャム パブリック リミテッド カンパニー イミダゾール誘導体およびｒａｆキナーゼ阻害剤としてのその使用
JP2003525936A (ja) * 2000-03-06 2003-09-02 スミスクライン ビーチャム パブリック リミテッド カンパニー Ｒａｆキナーゼ阻害物質としてのイミダゾール誘導体
GB0112348D0 (en) * 2001-05-19 2001-07-11 Smithkline Beecham Plc Compounds
US20040192689A1 (en) * 2001-09-05 2004-09-30 Dean David Kenneth Heterocycle-carboxamide derivatives as raf kinase inhibitors
TW200639163A (en) * 2005-02-04 2006-11-16 Genentech Inc RAF inhibitor compounds and methods

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WO2000025791A1 (fr) * 1998-11-04 2000-05-11 Smithkline Beecham Corporation Pyrazines substitues pyridin-4-yle ou pyrimidin-4-yle
WO2001066540A1 (fr) * 2000-03-06 2001-09-13 Smithkline Beecham P.L.C. Derives d'imidazol-2-carboxamide utilises comme inhibiteurs de kinase raf

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2000025791A1 (fr) * 1998-11-04 2000-05-11 Smithkline Beecham Corporation Pyrazines substitues pyridin-4-yle ou pyrimidin-4-yle
WO2001066540A1 (fr) * 2000-03-06 2001-09-13 Smithkline Beecham P.L.C. Derives d'imidazol-2-carboxamide utilises comme inhibiteurs de kinase raf

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8304557B2 (en) 2007-06-05 2012-11-06 Takeda Pharmaceutical Company Limited Fused heterocycle derivatives and use thereof
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2009025358A1 (fr) 2007-08-23 2009-02-26 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
US8324395B2 (en) 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8344135B2 (en) 2007-08-29 2013-01-01 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2010064611A1 (fr) 2008-12-01 2010-06-10 武田薬品工業株式会社 Composé hétérocyclique et applications
US8697874B2 (en) 2008-12-01 2014-04-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2010064722A1 (fr) 2008-12-02 2010-06-10 Takeda Pharmaceutical Company Limited Dérivés de benzothiazole convenant comme agents anticancéreux
US8143258B2 (en) 2008-12-02 2012-03-27 Takeda Pharmaceutical Company Limited Benzothiazole compounds useful for Raf inhibition
US8497274B2 (en) 2008-12-02 2013-07-30 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

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EP1432702A1 (fr) 2004-06-30
JP2005505563A (ja) 2005-02-24
ATE336489T1 (de) 2006-09-15
US7297693B2 (en) 2007-11-20
EP1432702B1 (fr) 2006-08-16
DE60214019T2 (de) 2007-01-18
US20040209883A1 (en) 2004-10-21
GB0121494D0 (en) 2001-10-24
ES2268110T3 (es) 2007-03-16

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